Composite expandable device with impervious polymeric covering and bioactive coating thereon, delivery apparatus and method

ABSTRACT

A composite expandable device for delivery into a vessel carrying blood comprising an expandable support frame having first and second end portions. An impervious polymer sleeve having inner and outer surfaces extending over the support frame. A coating is disposed on at least one of the inner and outer surfaces of the polymer sleeve for enhancing endothelial cell growth on the device and polymer sleeve.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. patent application Ser. No. 09/935,417filed Aug. 22, 2001 which is a continuation of U.S. patent applicationSer. No. 09/385,691 filed Aug. 30, 1999, now U.S. Pat. No. 6,371,980issued Apr. 16, 2002, the contents of which are incorporated herein intheir entirety.

BACKGROUND OF THE INVENTION

This invention relates to a composite expandable device with a polymericcovering on the device and a bioactive coating on device and thepolymeric covering, a delivery apparatus and a method.

Saphenous vein grafts have heretofore been utilized for bypassingoccluded arterial blood vessels in the heart. Because they are veintissue rather than arterial tissue, they have different characteristicsand generally do not function well long term as arterial vessels.Saphenous bypass veins are less muscular and are generally quite flimsyand compliant. When these saphenous vein grafts become diseased withage, stenoses and obstructive deposits which are cheesy or buttery inconsistency and which are very malleable are formed which cannot betreated effectively with interventional catheter procedures even whenfollowed with a stent implant. The plaque material forming the stenosistends to ooze through the stent struts and reoccludes flow passagethrough the stent and the saphenous vein graft. Other vascularobstructions, such as in femoral and popliteal vessels and in carotidsas well as in native coronary arteries also suffer from occlusions. Inmany of these cases, plaque proliferates through the stents when stentsare deployed in the vessels. Therefore a great need exits for a new andimproved device and method to provide a lasting therapeutic relief insuch situations.

SUMMARY OF THE INVENTION

In general, it is an object of the present invention to provide acomposite expandable device with a substantially impervious polymericcovering thereon with a bioactive coating on the device and covering anda method for using the same which can be utilized for treatingocclusions or partial occlusions in blood vessels and particularlysaphenous vein grafts.

Another object of the invention is to provide a device of the abovecharacter which will provide a lasting therapeutic solution to theoccurrence of plaque in stents in saphenous vein grafts.

Another object of the invention is to provide a device of the abovecharacter which can be used for repaving with endothelial cells theportion of the vessel being treated.

Another object of the invention is to provide a device of the abovecharacter which has physical characteristics which substantially matchor mimic the physical characteristics of blood vessels.

Another object of the invention is to provide a device of the abovecharacter in which a uniformly distributed structural support isprovided for the polymeric covering.

Another object of the invention is to provide a device of the abovecharacter which is very flexible and can bend axially to accommodate thetortuosity of blood vessels.

Another object of the invention is to provide a device of the abovecharacter which can be placed in tandem with another similar device in avessel to treat a long stenosis in a vessel.

Additional objects and features of the invention will appear from thefollowing description in which the preferred embodiments are set forthin detail in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side elevational view of a composite expandable device witha polymeric covering and a bioactive coating thereon, with certainportions broken away, mounted on a balloon delivery catheter.

FIG. 2 is a cross-sectional view taken along the line 2-2 of FIG. 1.

FIG. 3 is a cross-sectional view taken along the line 3-3 of FIG. 1.

FIG. 4 is an enlarged detail view of the balloon with the compositeexpandable device mounted thereon shown in FIG. 1.

FIG. 5 is a plan view of the expandable device which has been splitapart longitudinally and spread out to show its construction.

FIG. 6 is a side elevational view of another embodiment of a compositeexpandable device with polymeric covering and bioactive coating thereonwhich is tapered and is carried by a tapered balloon for expansion anddelivery.

FIG. 7 is a schematic illustration of a heart showing the manner inwhich a saphenous vein graft is treated utilizing the compositeexpandable device of the present invention.

FIG. 8 is an enlarged detail view showing the docking of a taperedcomposite expandable device being docked with a cylindrical compositeexpandable device.

FIG. 9 is a flow chart showing the method of the present invention.

FIG. 10 is a cross-sectional view of a medical device having a surfacetreated in accordance with the present invention.

DETAILED DESCRIPTION

In general, the composite expandable device incorporating the presentinvention is for delivery into a vessel carrying blood and comprises anexpandable support frame having first and second ends. An imperviouspolymer sleeve extends over the support frame and may leave the firstand second ends of the support frame exposed. A bioactive coating isprovided on one or both of the inner and outer surfaces of the polymersleeve and the frame for enhancing endothelial cell growth on the bloodcontact surfaces of the polymer sleeve and frame.

More in particular, the composite expandable device 11 as shown ismounted on a delivery apparatus 12 which consists of an expandableballoon 13 mounted on the distal extremity of a shaft or catheter 14 andhaving a wye fitting 16 mounted on the proximal extremity. The shaft orcatheter 14 is provided with a central lumen 17 which is adapted toreceive a conventional guide wire 18 through a port 19 provided in thefitting 16. The catheter shaft 14 is provided with a concentric lumen 21which is in communication with a port 22 of the fitting 16. The lumen 21extends through the balloon 13 and an opening (not shown) is provided inthe shaft 14 within the balloon for inflating and deflating the balloon.

The composite expandable device 11 consists of an expandable frame 26which has a polymeric sleeve 27 covering the same. The sleeve has folds28 therein when the frame is in an unexpanded condition as shown in FIG.4.

The expandable balloon 13 has a substantially continuous diameter and isprovided with distal and proximal portions 31 and 32 and an intermediateportion 33 which serves as a working portion of the balloon, having alength which will accept the length of the composite device 11. Theballoon 13 is provided with folds 34 when deflated as shown in FIGS. 1,3 and 4. Radiopaque marker bands 36 and 37 are provided on the portionof the shaft 14 extending through the balloon 13 and are mounted in thedistal and proximal portions 31 and 32 as shown adjacent to theintermediate portion 33. These marker bands 36 and 37 are within thedistal and proximal portions 31 and 32 of the balloon 13 but have adiameter which is substantially greater than the inner diameter of theintermediate portion 33 with the composite expandable device 11 mountedon the intermediate portion 33 to serve as stops or abutments to preventthe composite expandable device 11 from inadvertently slipping off ofthe balloon 13 during positioning and deployment of the compositeexpandable device 11.

The frame 26 which forms a part of the composite expandable device 11consists of a plurality of circumferentially spaced-apart elongatedstruts 41 having first and second ends 42 and 43. Foldable links 46 aresecured to the first and second ends 42 and 43 and extendcircumferentially of the frame 26 and serve in conjunction with theelongate struts to form a circular belt 47. As shown in FIG. 4, aplurality of serially-connected belts 47 are provided which are axiallyaligned with each other.

Sinusoidal-shaped end portions 48 and 49 are provided on opposite endsof the plurality of serially-connected belts 47. Interconnecting means50 is provided for interconnecting the plurality of belts 47 and the endportions 48 and 49 so that the belts 47 and end portions 48 and 49extend along an axis while permitting axial bending between the belts 47and the end portions 48 and 49 while maintaining a constant length ofthe device 11. The means 50 consists of at least one strut 51 which isrelatively short in length in comparison to the length of the elongatestruts 41 and a plurality of S-shaped links 52. Thus, as shown in FIG.5, between each end portion and a belt and between adjacent belts thereis provided a single strut 51 and two S-shaped links 52 all of which arespaced 120.degree. apart the interconnecting means between adjacentbelts and/or end portions are offset by 60.degree. Thus, with theconstruction shown in FIG. 4 there are provided four belts 47 and twoend portions 48 and 49 with five sets of interconnecting means 50.

It can be seen that the length of the frame 26 can be readily increasedor decreased by changing the number of belts 47 provided in the frame26.

The frame 26 can be formed of a suitable material such as a metal orplastic. Suitable metals are stainless steel, titanium, and alloysthereof and other biocompatible metals. The plastic can be a polymer.Since the frame to be utilized in the composite expandable device istypically used in a saphenous vein graft, it need not have the radialstrength normally required for stents placed in native arterial vessels.The frame 26 has been specifically designed to support the polymersleeve 27 for use in a saphenous vein graft to closely approximatemechanical properties of the saphenous vein graft. The same principlescan be used for a composite device for arterial vessels and other bloodvessels. Thus the frame 26 provides the necessary strength andconsistency throughout its length while giving good flexibilitythroughout its length to accommodate movement of the saphenous veingraft.

As shown in FIG. 4, the polymer sleeve extends over substantially theentire length of the frame 26 but leaving end portions 48 and 49substantially exposed for a purpose hereinafter described. The sleeve 27typically is formed of a suitable polymer. One polymer found to beparticularly satisfactory is PTFE which is supplied as a tube having awall thickness ranging from 0.002″ to 0.010″ and preferably 0.004″ to0.008″ and having a suitable original diameter as for example 2 to 4.5mm. The expanded PTFE material should have a pore size of approximately10 to 50 .mu.m.m. In addition in certain applications of this device, itmay be desirable that the material be expandable from two to six timesits original size yet retain elasticity properties to remain tightlyover and in close engagement with the frame 26 prior to and afterexpansion. After placing the sleeve 27 over the working or intermediateportion 33 of the balloon, the sleeve 27 may be secured to the frame 26so that it does not move axially of the frame 26 during deployment ashereinafter described. To accomplish this, the sleeve 27 can be wrappedinto a fold or a wing 28 and held in place along a line 61 (see FIG. 3)or tacked by spaced-apart heat seals (not shown) that are easilyrupturable upon expansion of the frame 26. It has been found that suchtacking by the use of heat seals on a fold or wing of the polymer sleeve27 makes it easy for the balloon 13 when expanding to open the sleeve 27without any significant additional balloon pressure being required.

With such a construction as shown in FIG. 3, the frame 26 which has beencrimped onto the intermediate portion 33 of the balloon 13 and thesleeve 27 wrapped over onto the same and seamed into place will have anoverall profile which has a diameter or size which is not greater thanor desirably less than the diameters of the proximal and distal portions31 and 32. Since the marker bands 36 and 37 have larger diameters thanthe intermediate portion 33 of the balloon 13, they will ensure that thecomposite expandable device consisting of the frame 26 and the sleeve 27cannot inadvertently slip off of the balloon 13 during the procedure.

Another embodiment of a composite expandable device incorporating theinvention is in the device 71 shown in FIG. 6. It is tapered rather thancylindrical to more closely approximate natural vessel geometry. In thisdevice 71, a frame 72 is provided which is constructed in substantiallythe same manner as frame 26 but with the belts 73 increasingsuccessively in circumference in one direction along the axis of thedevice 71 by providing foldable links 46 of successively greater lengthsto provide the tapered construction shown in which one expandable endportion 76 has a lesser diameter than the other end portion 77. Themeans connecting the belts 73 and the end portions 76 and 77 are likethe interconnecting means 50 hereinbefore described.

A tapered polymer sleeve 81 is provided on the exterior of the frame 72while leaving the end portions 76 and 77 substantially exposed. Atapered balloon 86 is disposed within the frame 72 and is utilized forexpanding the composite expandable device 71. The tapered balloon 86 ismounted on the distal extremity of a balloon shaft or catheter 87 and isconstructed in the same manner as balloon shaft 14 and provides adelivery apparatus 89.

In order to provide a cell-friendly surface or surfaces on the sleeves27 and 81, at least one surface of the outer and inner surfaces andpreferably both inner and outer surfaces are treated in the mannerdescribed in co-pending application Ser. No. 09/385,692 filed Aug. 30,1999.

In general the method of the present invention is for treating a medicaldevice having at least one surface exposed to tissue and/or blood andcomprises the steps of subjecting the one surface to a low temperatureplasma of an appropriate chemical agent to provide a plasma depositedlayer having functional groups like amine, carboxylic, or hydroxylgroups covalently bound to the surface of the device. The plasmadeposited layer is then subjected to a chemical treatment withmultifunctional linkers/spacers which then become covalently bound withthe plasma deposit layer. A bioactive coating is then covalently boundto spacers/linkers.

More in particular, the method of the present invention as hereinafterdescribed utilizes a plasma chamber (not shown) of the type as describedin U.S. Pat. No. 5,643,580 well known to those skilled in the art andthus will not be described in detail. Typically the plasma utilized inthe method of the present invention utilizes a “low temperature” or“cold” plasma produced by glow discharge. A low temperature plasma iscreated in an evacuated chamber refilled with a low pressure gas havinga pressure on the order of 0.05 to 5 Torr and with the gas being excitedby electrical energy usually in the radio frequency range. A glowdischarge is created typically in the range of 2-300 watts for low powerand 50-1000 watts for high power depending on the chamber volume.

The steps for the method of the present invention are shown in FIG. 9for the treatment of a substrate 111 shown in FIG. 10 and having firstand second surfaces 112 and 113. The substrate 111 is part of a medicalimplant or medical device that has at least one surface which is to betreated, such as one of the surfaces 112 and 113, to achieve desirablebiological activities on that surface. The substrate 111 is formed of asuitable material such as a fluorinated thermoplastic or elastomer ormore specifically, by way of example, PTFE. The latter material isparticularly desirable where the medical implant or medical device is inthe form of small-diameter vascular grafts. The substrate can also beformed of any polymer and polymer composites, metals and metal-polymercomposites.

Let it be assumed that the surface 112 of the substrate 111 is to betreated in accordance with the method set forth in FIG. 9. The surface112 is cleaned in an oxygen or air plasma as shown by step 116 in arelatively short period of time. The plasma cleaning process is anablation process in which radiofrequency power, as for example 50-1000watts, under a higher pressure e.g. 0.1 to 1.0 Torr at a high flow rate,as for example of at least 50 cc. per minute gas passing through theplasma chamber. Such a cleaning process can use oxygen, alone, a mixtureof oxygen with argon or nitrogen for a period of time of up to 5minutes. Thus, a plasma of oxygen air, or inert gases can be utilizedfor plasma cleaning.

Thereafter, the surface 112 after being cleaned as shown in step 117, isfunctionalized by subjecting the surface 112 to a pure gas or gasmixture plasma to assist in the deposition of functional groups on thesurface 112 to provide a deposited layer 118 which is covalently boundto the surface 112. Other methods which can be utilized in place of theplasma deposition step 117 include a modification by irradiation withultraviolet or laser light in the presence of organic amine orhydrazine. The plasma deposition step 117 used to achieve activation ofthe surface utilizes precursor gases which can include the followinginorganic and organic compounds: NH₃ (ammonia), N₂ H₄ (hydrazine)aliphatic amines, aliphatic alcohols, aliphatic carboxylic acids,allylamine, water vapor, allyl alcohol, vinyl alcohols, acrylic acid,methacrylic acid, vinyl acetate, saturated or unsaturated hydrocarbonsand derivatives thereof. Precursors can be saturated (aliphatic amines,aliphatic alcohols, aliphatic acids) or unsaturated (allyl, vinyl andacrylated compounds). Employing unsaturated precursors or operatingpulsed plasma (single mode or gradient) tend to preserve functionalgroups rather than form defragmentation products, having the potentialof introducing a significantly higher percentage of reactive groups.

The deposition step 117 can be performed in continuous or pulsed plasmaprocesses. The power to generate plasma can be supplied in pulsed formor can be supplied in graduated or gradient manner, with higher powerbeing supplied initially, followed by the power being reduced or taperedtowards the end of the plasma deposition process. For example, higherpower or higher power on/off ratios can be utilized at the beginning ofthe step 117 to create more bonding sites on the surface 112 whichresults in stronger adherence between the substrate surface 112 and thedeposited layer 118. Power is then tapered off or reduced as for exampleby reducing the power-on period to obtain a high percentage offunctional groups on the surface 112.

The plasma deposition layer 118 created on the surface 112 has athickness ranging from 5-1000 .ANG. By way of example this can be alayer derived from allylamine plasma. This plasma-assisted depositiontypically is carried out at a lower power that ranges from 2-400 wattsand typically from 5-300 watts depending upon the plasma chamber size,pressure and gas flow rate. This step 117 can be carried out for aperiod of time ranging from 30 seconds to 30 minutes while being surethat the reactive group created is preserved.

When it is desired to retain only those functional groups in the layer118 which have established stable bonds to the substrate surface 112, asfor example to a PTFE surface, an optional step 121 can be performed byrinsing or washing off loosely bound deposits with solvents or buffers.Thus, deposits which are merely adsorbed on the surface 112 are rinsedand washed off and the covalently bound deposits remain on the surface.Such a step helps to ensure that parts of the coating forming the layer118 cannot thereafter be washed off by shear forces or ionic exchangeswith blood flow passing over the surface.

Plasma-assisted deposition has been chosen because it is a clean,solvent-free process which can activate the most inert substrates likePTFE. Plasma produces high energy species, i.e., ions or radicals, fromprecursor gas molecules. These high energy species activate the surface112 enabling stable bondings between the surface 112 and activatedprecursor gas. Allylamine has been chosen as a precursor for theplasma-assisted deposition step because it has a very low boiling pointof 53° C., making it easy to introduce as a gas into the plasma chamber.By using allylamine, the desire is to have radicals created by tileplasma occurring preferentially at C.dbd.C double bonds so that the freeamine groups created are preserved for other reactions as hereinafterdescribed. Also, it is believed to give a high yield of the desiredprimary amine group on the surface 112.

In the rinsing step 121, a solvent rinse such as dimethylsulfoxide(DMSO) is used for removing all of the allylamine deposit which has notbeen covalently bound to the surface 112, i.e. to remove any allylaminewhich has only been adsorbed on the surface. Another material such asdimethylformamide (DMF), tetrahydrofuran (THF) or dioxane can beutilized as a solvent rinse. In addition, for removing polar deposits, abuffer rinse can be utilized. As soon as the rinsing step 121 has beencompleted and the substrate 111 dried, wetting or surface tensionmeasurement showed very hydrophilic PTFE (layer 118) completely wet withwater. The presence of free amine groups can be visualized by taggingfluorescent probes reactive with amine groups. ATR-FTIR (attenuatedtotal reflectance-fourier transform infrared) or ESCA (electronspectroscopy for chemical analysis) may give information about thepresence of amine or nitrogen in layer 118, respectively.

Subsequently, in step 123, homo or hetero multifunctionallinkers/spacers react and form stable linkages with the functionalgroups in layer 118 obtained by the plasma-assisted deposition process.This treatment in step 123 serves to provide linkers/spacers asrepresented by symbols 126 in FIG. 10 to improve accessibility ofcoating agents, as for example peptides and proteins, to functionalgroups on substrates. Vice versa, it is believed that the linkers 126enhance the exposure of peptides and proteins to the environment. Alsothe linkers give peptides or proteins in the final coating more spaceand freedom to assume their natural conformations. As a result, thecovalently bound coating agents are more likely to maintain theirnatural conformations and therefore their bioactivity.

By way of example, primary amine groups obtained after allylamine plasmareact with succinic anhydride leading to a substrate covered by linkers126 ended with COOH groups. Thus, the coverage with linkers 126 is lessthrombogenic and more cell-friendly compared to the coverage with NH₂rich layer 118. The linker/spacer attachment step 123 can also beutilized to introduce desirable functional groups which can readilyreact with the final coating agents. For example, COOH groups at the endof linker 126 can form stable amide linkage with NH₂ groups incell-adhesion peptides and proteins, anti-inflammatory peptides,anti-thrombogenic peptides and proteins, growth factors, etc. The COOHgroups can also form an ester linkage with OH groups in theanti-coagulant agent heparin. Taking the nature of the substrate,functional groups obtained after plasma, the availability of functionalgroups and the size and nature of the final coating agents intoconsideration, the chemistry and size of the linkers may be selected.Multifunctional linkers usually have 2-20 carbon atoms in the backbone.They can be anhydrides of dicarboxylic acids, dicarboxylic acids,diamines, diols, or amino acids. Linkers can be just one molecule, astring of several molecules, such as a string of amino acids, a stringof alternate dicarboxylic acids-diamines, dicarboxylic acids-diols oranhydrides-diamines. This chemical treatment step 123 hereinbeforedescribed can also be characterized as one that introduces otherdesirable functional or activating groups.

Organic solvents which are miscible with water can be used as solubilityenhancers to facilitate coupling efficiency between the plasma-treatedsubstrate and the linkers (step 123) and/or coating agents (step 128) inan aqueous medium. DMSO, DMF or dioxane can be used as such solubilityenhancers. They facilitate the contact between functional groups presentin molecules of different hydrophilicity or hydrophobicity. After thecorresponding functional groups come close enough to each other,chemical reactions between them can occur. So, solubility enhancers inan aqueous solution can augment the binding reactions. The solubilityenhancers may also enhance the accessibility of the linker/coatingagents to the functional groups on porous surfaces.

After completion of the wet chemistry linker/spacer attachment step 123,the wetting behavior/surface tension of the resulting surface can beanalyzed. Appropriate techniques, such as ESCA, SIMS, ATR-FTIR can beused to characterize the hydrophilic surface created in step 123.Fluorescent imaging of functional groups can also be carried out.

The bioactive/biocompatible coating step 128 can be carried out toprovide the final layer of coating 131 on the surface 112 of thesubstrate 111 (as shown in FIG. 10). In this step, the availablefunctional groups provided by the linkers 126, are used to covalentlybind molecules of a bioactive/biocompatible agent, such as acell-adhesion peptide P15 as hereinafter described, possessing desirableproperties to the substrate surface 112 to provide the final resultingcoating on the surface 112 as for example a PTFE surface. Of interestare bioactive/biocompatible coatings which, among others, can reduceforeign body reactions, accelerate the functioning and integration, aswell as increase the long-term patency of implants. Such coatings caninclude cell adhesion peptides, proteins or components of extra-cellularmatrix to promote cell migration and proliferation, leading to a rapidand complete coverage of the blood-contacting surface by a naturalendothelial cell lining. Coatings with growth factors such as VEGF maylead to similar results. Non-adhesive coatings with polyethylene glycolderivatives are used for biocompatible hydrophilic surfaces asseparation membranes, immuno barriers or surfaces free of plateletadhesion. Also, anti-thrombogenic coatings with hirudin, hirudinanalogs, reversible and irreversible thrombin inhibitor peptides, oranti-coagulant coatings with heparin are desirable to reduce or preventthrombosis formation at the implanting site. These localanti-thrombogenic or anti-coagulant coatings are more preferable than asystemic anti-coagulant treatment. Anti-inflammatory coatings can beused because occlusions may originate at inflamed sites.Anti-proliferative coatings are another way to reduce vessel occlusionsby preventing smooth muscle cell proliferation.

Chemical/biological testing such as AAA (amino acid analysis), in vitrocell cultures followed by SEM (scanning electron microscopy), and invivo testing can be used for evaluating the coatings of the presentinvention.

A specific example of a coating having biological activity and medicalimplants having a surface carrying the same and the method incorporatingthe present invention may now be described as follows.

Let it be assumed that it is desired to coat long porous PTFE tubes, asfor example having a length of 11 cm., which are to be utilized asmedical implants and to be treated with a coating using the method ofthe present invention. The tubes can be prepared for treatment bymounting the same on an anodized aluminum wire frame and then insertingthem in a vertical position in the upper portion of the plasma chamberbeing utilized. The tubes are then cleaned in an air plasma by operatingthe plasma chamber at 0.3 torr at 50 watts for 3 minutes. After theplasma cleaning operation has been performed, the chamber is flushedwith allylamine gas at 0.2 torr for 10 minutes. Allylamine plasma isthen created at 0.2 torr at 15 watts for 30 minutes. Radiofrequencypower is turned off and allylamine is permitted to flow at 0.2 torr for2 minutes. The allylamine flow after plasma treatment is provided toreact with any free radicals on the PTFE. The allylamine flow is thenterminated and a vacuum is maintained in the chamber for 15 minutes.Thereafter, the pressure in the plasma chamber is increased toatmospheric pressure. The tubes being treated are then removed from thechamber and transferred to clean glass rods. The tubes are thensubmerged and rinsed in an appropriate volume of DMSO. The samples arethen removed from the DMSO rinse and washed with deionized (DI) waterand optionally ultrasonically at room temperature for 3 minutes.

In the covalent linker attachment step 123, a 1 M (one molar) succinicanhydride solution is prepared using DMSO and placed in a covered glasstray container. The plasma treated and optionally rinsed tubes are thensubmerged in the succinic anhydride solution in the glass tray containerand subjected to an ultrasonic mix at 50° C. in order to bring thesuccinic anhydride into close proximity to the free amine groups on thePTFE surface. A one molar (1M) Na₂ HPO₄ solution in DI water is used toadjust the pH between 6 to 9, preferentially pH 8. A higher pH resultsin a faster reaction. This reaction between the free amine groups andthe succinic anhydride can be carried out between room temperature and80° C. and preferentially between 20-50° C.

After this has been accomplished, the tubes are removed and rinsed withDI water optionally utilizing ultrasound. The tubes are then dried withnitrogen.

Let it be assumed that a peptide coating is desired to be applied to thesurface thus far created. Solubility enhancers such as DMSO and DMF canbe added between 0-50 volume/volume v/v %, preferentially 10-30%. A 90mL. DI water/DMSO solution is prepared by taking 70 mL. of DI water andmixing the same in a glass container with 20 mL. of DMSO. The driedtubes are then placed in the DMSO solution and ultrasonically mixed fora period of 1 minute.

Freshly prepared EDC [N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride] (Fluka) solution in 5 ml DI water is poured over thetubes submerged in water/DMSO to activate COOH groups on the PTFEsurface. After 0.5-3 min., P15((H-Gly-Thr-Pro-Gly-Pro-Gln-Gly-Ile-Ala-Gly-Gln-Arg-Gly-Val-Val-OH)acetate salt, GLP grade peptide) solution in 5 ml DI water is added. Forhydrophobic peptides, the peptides may be dissolved in an organicsolvent miscible with water (DMSO, DMF or dioxane). EDC and P15 amountsare based on the following final concentrations: 0.02 M EDC to be usedand 0.0002 M P15 in the final reaction volume, i.e. 100.times. molarexcess of EDC to P15. The reaction at room temperature is carried outbetween 1-16 hours, preferentially 2-8 hours. The tubes are then rinsedseveral times with deionized water with an optional one minuteultrasonic treatment. The tubes are then dried with nitrogen gas. Thetubes are then inverted to bring the coated side to the inside. Aminoacids analysis revealed that up to 1.5 nmol P15/cm.sup.2 was bound tothe PTFE surface.

From the foregoing it can be seen that there has been provided a coatingwhich has biological activities which can be utilized on surfaces ofmedical implants and devices and a method for accomplishing the same.The coating and method can be utilized on many different types ofdevices which are intended to be implanted in the human body or in otherwords to remain in the human body for a period of time. Such devicesinclude stents and grafts placed in various vessels of the human body.Other medical devices such as heart valves, defibrillators and the likehave surfaces which are candidates for the coating and method of thepresent invention. The coating and method is particularly advantageousfor use on surfaces which heretofore have been difficult to obtain cellgrowth on, as for example PTFE and ePTFE. By utilizing the coating andmethod of the present invention, it has been found that cell growth hasbeen greatly enhanced, making possible long term implantation of saiddevices in the human body.

Thus the surface of the polymer can be characterized as having appliedthereto a bioactive coating which is cell friendly and which enhancesgrowth of cells thereon. As described therein, a low temperatureplasma-deposited layer is provided on the surface of the polymer tofunctionalize the surface and provide free amine groups thereon. Aspacer/linker molecular layer is covalently bonded to theplasma-deposited layer. A peptide coating such as P15(Gly-Thr-Pro-Gly-Pro-Gln-Gly-Ile-Ala-Gly-Gln-Arg-Gly-Val-Val; SEQ IDNO: 1) is deposited on the spacer/linker layer. By way of example, theouter surface of the sleeve 27 can be treated first. Thereafter, thesleeve 27 can be inverted by turning it inside out and treating theinside surface which is now outside. Alternatively, both the outside andinside surfaces can be treated at the same time.

Operation and use of the composite expandable devices 11 and 71 with thedelivery apparatus 12 and delivery apparatus 89 may now be brieflydescribed as follows. In this connection let it be assumed that a humanheart 101 as shown in FIG. 6 has previously had a coronary artery 102 inwhich there had been formed therein a substantially total occlusion 103.Also let it be assumed that it was found necessary to perform a bypassoperation and to insert a saphenous vein graft utilizing a length ofsaphenous vein 106 which has one end connected into the aorta 107 of theheart by a proximal anastomosis 108 for a blood supply and bypassing thecoronary artery occlusion 103 and making a connection to the coronaryartery 102 at a distal anastomosis 109. Now let it be assumed that aftera period of time there has been a build-up of plaque forming a stenosisin the saphenous vein graft 106 in the region near the distalanastomosis 109.

With such a condition, it is desirable to first use a tapered compositeexpandable device 71, delivering the same by the use of the taperedballoon 86 of the delivery apparatus 89 on a guide wire in aconventional manner through the femoral artery into the aorta, thenthrough the proximal anastomosis 108 and then advanced into a regionadjacent the distal anastomosis 109. The distal tapered balloon 86 isthen expanded to expand the device 71 into engagement with the wall ofthe saphenous vein graft and to thereby enlarge the opening through thesaphenous vein graft to enhance blood flow therethrough, through theflow passage formed by the device 71. Thereafter, the tapered balloon 86and the delivery apparatus 89 is removed.

Let it be assumed that the tapered device 71 has an inadequate length totreat the entire stenosis and it is desired to place another compositeexpandable device as for example the device 11 (FIG. 1) in tandem or inseries with the device 71. Assuming that the guide wire is in place thatwas used for deploying the first device 71, the shaft 14 of the deliveryapparatus 12 can be threaded over the guide wire 18 and a balloon with acomposite expandable device 11 mounted thereon advanced into thesaphenous vein graft 106 until the distal extremity of the device 11meets within the proximal larger end 77 of the device 71. The distalextremity can be docked into the open proximal end of the device 71.Thereafter, the balloon 13 can be expanded to complete the docking ofthe distal extremity of the device 11 in the proximal extremity of thedevice 71 so that they are deployed in the saphenous vein graft 106 intandem. The balloon 13 then can be deflated and removed with thedelivery apparatus 12 along with the guide wire 18. The positioning ofthe devices 71 and 11 can be observed fluoroscopically by observing thelocations of the radiopaque markers 56 provided on the devices 11 and71. If the occlusion in the saphenous vein graft is sufficiently long,an additional device 11 can be placed in tandem with the device 11already in place. If this is desired, the guide wire can be left inplace and another balloon delivery apparatus 12 with a device 11 mountedthereon can be advanced into the saphenous vein graft 106 and the distalextremity docked into the expanded proximal extremity of the alreadypositioned device 11. The balloon 13 can be deflated and then removedalong with the guide wire 18 and the femoral artery closed in anappropriate manner.

From the foregoing it can be seen that the balloon expandable devices 11and 71 form a vascular prosthesis which has mechanical and biomedicalproperties which re-establish and mimic the composition of thebiological function and environment of a healthy natural vessel as forexample a recently transplanted saphenous vein graft. The support framefor the polymer sleeve is designed to provide adequate support for thepolymer sleeve while still providing appropriate compliancecorresponding to that of the vessel in which it is disposed. The devicewith its free outer ends is capable of firmly engaging the wall of thevessel in which it is disposed to ensure that the device remains inplace in the desired position within the vessel after deployment. By theuse of cylindrical and tapered devices, it is possible to construct avascular prosthesis which corresponds to the natural geometry of thevessel. The delivery apparatus has a low profile which by utilizing aballoon having an intermediate working portion of a lesser diameterretains this low profile even when the composite expandable device ismounted thereon to facilitate positioning and deployment of the deviceto the site. Use of the polymer sleeve in the device prevents plaque ordeposits within the blood vessel as for example a saphenous vein graftfrom oozing through the interstices of the frame so that there isunimpeded blood flow through the expanded frame. By covering the polymersleeve with a peptide such as P15, endothelial cell growth isstimulated. In this way, it is possible to repave the vessel withendothelial cells, nature's most blood compatible surface, and helpprevent further spread or degradation of the lumen in the vessel at thatsite. The construction of the device permitting axial bending makes itpossible for the expanded device to readily flex with the vessel.

1. An expandable device for delivery into a blood vessel carrying bloodcomprising: an expandable support frame having first and second endportions, a polymer sleeve having inner and outer surfaces and where thepolymer sleeve comprises a polymer that is difficult to obtainendothelial cell growth thereon, and a coating having a first layercapable of providing free amine groups comprising a plasma activatedstable functional group, a second linker layer having a terminal COOHgroup, and a third cell adhesion peptide layer, wherein the linker layeris positioned between and covalently bonded to each of the first andthird layers, said coating carried on and attached to at least one ofthe inner and outer surfaces of the polymer sleeve for enhancingendothelial cell growth on the polymer sleeve, wherein second linkerlayer coverage with linkers having a terminal COOH group reduces athrombogenic risk of unbound linkers on the layer.
 2. The device ofclaim 1, wherein said coating is prepared by treating said inner andouter surface with a gaseous plasma cleaning process utilizingradiofrequency energy to ablate said inner or outer surface and tofunctionalize said inner or outer surface and to produce aplasma-deposited layer having functional groups, and subjecting saidplasma-deposited layer to multifunctional linkers in a wet chemicaltreatment to form covalent bonds between the linkers/spacers and thefunctional groups of the plasma-deposited layer to covalently bind thecell-adhesion peptides to said inner or outer surface of the substrate.3. The device of claim 1, wherein said cell-adhesion peptide has anamino acid sequence presented as SEQ ID NO:
 1. 4. The device of claim 2,wherein said cell-adhesion peptide has an amino acid sequence presentedas SEQ ID NO:
 1. 5. The device of claim 1, wherein a linker having aterminal COOH group binds one or more cell-adhesion peptides having anamino acid sequence presented as SEQ ID NO:
 1. 6. The device of claim 2,wherein a linker having a terminal COOH group binds one or morecell-adhesion peptides having an amino acid sequence presented as SEQ IDNO: 1.